Correspondence
Global Clinical Development Late R&I (PB) and Mortality up until day 42 (the
Global Patient Safety BioPharmaceuticals (MY),
AstraZeneca, Gaithersburg, MD, USA; Global
Medical BioPharmaceuticals (JM) and Global
Patient Safety BioPharmaceuticals (MN),
AstraZeneca, Gothenberg SE431 83, Sweden;
Global Medical BioPharmaceuticals, AstraZeneca,
Cambridge, UK (HGdS, HM, MA); Global Patient
Safety BioPharmaceuticals, AstraZeneca,
Bangalore, India (NKS)
1 Brighton Collaboration. Updated Proposed
Brighton Collaboration process for
developing a standard case definition for
study of new clinical syndrome X, as applied
to Thrombosis with Thrombocytopenia
Syndrome (TTS). May 18, 2021. https://
brightoncollaboration.us/wp-content/
uploads/2021/05/TTS-Interim-Case-
Definition-v10.16.3-May-23-2021.pdf
(accessed July 26, 2021).
2 Greinacher A, Thiele, T, Warkentin TE, et al.
Thrombotic thrombocytopenia after ChAdOx1
nCov-19 vaccination. New Engl J Med 2021;
384: 2092–101.
3 Burn E, Li X, Kostka K, et al. Background
rates of five thrombosis with
thrombocytopenia syndromes of special
interest for COVID-19 vaccine safety
surveillance: incidence between 2017 and
2019 and patient profiles from 20·6 million
people in six European countries. medRxiv
2021; published online May 13. https://doi.
org/10.1101/2021.05.12.21257083
(preprint).
4 Eslamifar Z, Behzadifard M, Soleimani M,
Behzadifard S. Coagulation abnormalities in
SARS-CoV-2 infection: overexpression tissue
factor. Thromb J 2020; 18: 38.
5 AstraZeneca. Vaxzevria, COVID-19 Vaccine
(ChAdOx1-S [recombinant]). Summary of
Product Characteristics. June, 2021.
https://www.ema.europa.eu/en/documents/
product-information/vaxzevria-previously-
covid-19-vaccine-astrazeneca-epar-
product-information_en.pdf (accessed
July 26, 2021).
6 Emary KRW, Golubchik T, Aley PK, et al.
Efficacy of ChAdOx1 nCoV-19 (AZD1222)
vaccine against SARS-CoV-2 variant of concern
202012/01 (B.1.1.7): an exploratory analysis of
a randomised controlled trial. Lancet 2021;
397: 1351–62.
7 Bernal JL, Andrews N, Gower C, et al.
Effectiveness of the Pfizer-BioNTech and
Oxford-AstraZeneca vaccines on covid-19
related symptoms, hospital admissions,
and mortality in older adults in England:
test negative case-control study. BMJ 2021;
373: n1088.
Voriconazole
See Online for appendix
pharmacogenetics
In their Article, Johan Maertens and
colleagues1 showed the results of
a randomised, controlled, phase 3
trial comparing posaconazole versus
voriconazole for the primary treat­
ment of invasive aspergillosis.
578
1 Maertens JA, Rahav G, Lee D-G, et al.
primary endpoint) was 44 (15%) of
288 patients for posaconazole versus
59 (21%) of 287 patients for
voriconazole.1 The overall incidence of
treatment-related adverse events was
10% higher with voriconazole than
with posaconazole.1
Therapeutic drug monitoring
was not done, and the CYP2C19
phenotype status of the patients was
unknown. However, voriconazole
(unlike posaconazole) is metabolised
by CYP2C19,2 and there is substantial
evidence linking the CYP2C19
genotype with phenotypic variability
in voriconazole pharmacokinetics.3,4
In patients for whom a rapid or
ultrarapid metaboliser genotype
is identified (carriers of one
or two CYP2C19*17 alleles;
5–30% of patients), the probability
of reaching therapeutic voriconazole
concentrations is very low. In such
cases, use of an alternative antifungal
agent, such as posaconazole, is
recommended.3 A strong association
between individuals who are slow
metabolisers (carriers of two no-
function CYP2C19*2 or CYP2C19*3
alleles; 2–15% of patients) and
increased voriconazole concentrations
resulting in adverse events is also
documented, which provides the basis
for recommending use of alternative
agents (eg, posaconazole) in these
patients.3
Considering the prevalence of rapid
and slow metaboliser phenotypes
within the general population, it is
likely that a sizeable proportion of
patients receiving voriconazole in
this study metabolised either rapidly
or slowly, which partly explains
the lower therapeutic response or
more frequent side-effects seen
with voriconazole compared with
posaconazole.
We declare no competing interests.
*Nicolas Pallet, Marie Anne Loriot
nicolas.pallet@aphp.fr
Service de Biochimie, Assistance Publique Hôpitaux
de Paris, Hôpital Européen Georges Pompidou,
F-75015 Paris, France
Posaconazole versus voriconazole for
primary treatment of invasive aspergillosis:
a phase 3, randomised, controlled,
non-inferiority trial. Lancet 2021;
397: 499–509.
2 Theuretzbacher U, Ihle F, Derendorf H.
Pharmacokinetic/pharmacodynamic profile of
voriconazole. Clin Pharmacokinet 2006;
45: 649–63.
3 Moriyama B, Obeng AO, Barbarino J, et al.
Clinical Pharmacogenetics Implementation
Consortium (CPIC) guidelines for CYP2C19 and
voriconazole therapy. Clin Pharmacol Ther 2017;
102: 45–51.
4 US Food and Drug Administration.
Prescribing information for voriconazole.
January, 2019. https://www.accessdata.fda.
gov/drugsatfda_docs/label/2019/021266
s039,021267s050,021630s029lbl.pdf
(accessed April 30, 2021).
Authors’ reply
Nicolas Pallet and Marie Anne Loriot
postulate that the CYP2C19 metaboliser
phenotype might contribute to lower
therapeutic response, or to more
treatment-related adverse events, or
both, with posaconazole than with
voriconazole.1
Here we summarise the explor­
atory pharmacogenetic testing, as
described in the Article. 1 Germline
DNA was obtained from consented
participants genotyped for CYP2C19
alleles CYP2C19*2–CYP2C19*8 and
CYP2C19*17. Participants with a
transplant history were excluded
because of the potential for a
confounding genotype, leaving
149 (52%) of 287 voriconazole
participants for analyses. The
objectives of the analyses included
determining the contribution of
CYP2C19 metaboliser phenotype
status to variability in the
efficacy and safety findings. The
primary efficacy measure was
day 42 mortality, whereas the safety
measure was the rate of treat­ment-
related adverse events. The CYP2C19
phenotypes for posaconazole and
voriconazole are listed in the
appendix. Among participants in the
voriconazole group, only one person
was identified as a poor metaboliser.
Given the very low number of poor
metabolisers, it was unlikely that the
reason for the more frequent side-
effects seen in this study could be
www.thelancet.com Vol 398 August 14, 2021

attributable to CYP2C19 metaboliser
phenotypes.
For this brief reply, descriptive
summaries are provided to evalu­
ate efficacy (day 42 mortality),
safety (treatment-related adverse
events), and CYP2C19 metaboliser
phenotypes. Given the small
numbers, the effects of reduced
enzyme activity (ie, results from the
poor and intermediate metabolisers)
and increased enzyme activity (ie,
results from the rapid and ultrarapid
metabolisers) were pooled. We found
trends in the opposite direction than
would be predicted if increased
CYP2C19 activity adversely affected
efficacy, as there were similar
mortality rates between participants
with reduced enzyme activity and
extensive metabolisers, and lower
mortality rates in participants
with increased enzyme activity
(appendix). Safety endpoints were
also evaluated. For voriconazole,
there was a weak trend in the
opposite direction than would be
predicted if reduced CYP2C19 activity
had adversely affected safety, with
higher rates of treatment-related
adverse events seen in participants
with increased enzyme activity.
Hepatic safety showed a trend in
the expected direction, with the
highest rate of treatment-related
adverse events among participants
with reduced enzyme activity and
the lowest among participants
with increased enzyme activity
(appendix). However, the relatively
small number of participants and
events decreased the precision of
these observations.
In summary, there were no clear
trends to support previous reports
of an association between CYP2C19
phenotype and voriconazole efficacy
or safety out­comes.1 However, given
the limita­tions of the small sample
sizes within this dataset, we cannot
convincingly conclude that such an
association does not exist.
JAM reports grants, personal fees, and
non-financial support from Merck Sharp & Dohme,
www.thelancet.com Vol 398 August 14, 2021
a subsidiary of Merck & Co, Gilead Sciences, and
Pfizer; and personal fees and non-financial support
from Mundipharma, F2G, Cidara, Basilea, and
Schering-Plough. HAW, RMW, and PMS are
employees of Merck & Co.
*Johan A Maertens, Hetty A Waskin,
Rachel Marceau West, Peter M Shaw
johan.maertens@uzleuven.be
Department of Microbiology, Immunology, and
Transplantation and Department of Haematology,
University Hospitals Leuven, 3000 Leuven,
Belgium (JAM); Department of Infectious Disease
(HAW), Department of Biostatistics and Research
Decision Sciences (RMW), and Department of
Genetics and Pharmacogenomics (PMS),
Merck & Co, Kenilworth, NJ, USA
1 Maertens JA, Rahav G, Lee D-G, et al.
Posaconazole versus voriconazole for primary
treatment of invasive aspergillosis: a phase 3,
randomised, controlled, non-inferiority trial.
Lancet 2021; 397: 499–509.
Trends in population
health and demography
Stein Vollset and colleagues fore­
casted that population increase in
sub-Saharan Africa will continue until
2100. Consequently, three of the
region’s countries will join Nigeria
among the ten most populous coun­
tries globally: DR Congo, Ethiopia,
and Tanzania.1 Although we applaud
the authors for including alternative
scenarios based on change in edu­
cational attainment and access to
contraception, the Article neglects safe
childbirth as a co-driver of decreasing
fertility rates.
According to Vollset and colleagues,
educational attainment and contra­
ceptive met need account for 80·5% of
the variance in cohort fertility at age
50 years.1 Including survival at birth as
a covariate might be seen as a minor
factor and difficult to predict; however,
neglecting this driver throughout the
Article risks presenting an unjustifiably
simplified solution for overpopulation.
Moreover, it could exacerbate the
dangerous misconception that saving
lives at birth leads to additional over­
population and accelerated climate
change.2
Across different cultures, when
parents see their offspring survive
Correspondence
childbirth and early childhood, they
start planning for fewer children than
originally intended and focusing on
optimising their education and social
circumstances. This dynamic, however,
can take time and is interlinked with
multiple other factors, such as a
decline in the need for child labour
and increased access to education and
contraception.3
Although other causes of child
mortality show promising declines,
the epidemic of stillbirths and early
neonatal deaths is underprioritised.
In addition to a strong ethical and
humanitarian imperative, ending this
global burden of more than 5 million
lost lives per year is forecasted to have
a positive effect on demography and
climate change.4,5
We declare no competing interests. This
Correspondence was written by members of the
PartoMa research team, which is funded by the
Danida Fellowship Centre, Ministry of Foreign
Affairs of Denmark, Copenhagen, Denmark.
David Turnley/Corbis/VCG/Getty Images
*Nanna Maaløe, Natasha Housseine,
Tarek Meguid, Siri Tellier,
Jos van Roosmalen,
Dan W Meyrowitsch,
Thomas van den Akker
nannam@sund.ku.dk
Global Health Section, Department of Public Health,
University of Copenhagen, Copenhagen 1353,
Denmark (NM, ST, DWM); Department of Obstetrics
and Gynecology, Hvidovre University Hospital,
Hvidovre, Denmark (NM); Medical College, East
Africa, Aga Khan University, Dar es Salaam, Tanzania
(NH); Kivunge Hospital, Zanzibar, Tanzania (TM);
Athena Institute, VU University, Amsterdam,
Netherlands (JvR, TvdA); Department of Obstetrics
and Gynaecology, Leiden University Medical Center,
Leiden, Netherlands (JvR, TvdA)
1 Vollset SE, Goren E, Yuan C-W, et al.
Fertility, mortality, migration, and population
scenarios for 195 countries and territories
from 2017 to 2100: a forecasting analysis for
the Global Burden of Disease Study. Lancet
2020; 396: 1285–306.
2 Rosling H, Rönnlund AR, Rosling O.
Factfulness: ten reasons we’re wrong about
the world—and why things are better than you
think. New York, NY: Flatiron Books, 2018.
3 Omran, A. The epidemiologic transition.
A theory of the epidemiology of population
change. Milbank Mem Fund Q 1971; 49: 509–38.
4 You D, Hug L, Ejdemyr S, et al. Global, regional,
and national levels and trends in under-5
mortality between 1990 and 2015,
with scenario-based projections to 2030:
a systematic analysis by the UN Inter-agency
Group for Child Mortality Estimation. Lancet
2015; 386: 2275–86.
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